Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner

Nat Commun. 2019 Feb 22;10(1):910. doi: 10.1038/s41467-019-08886-8.


Oncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis*
  • Adaptor Proteins, Signal Transducing / genetics
  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / pathology*
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cell Cycle Proteins / biosynthesis*
  • Cell Cycle Proteins / genetics
  • Cell Line, Tumor
  • Checkpoint Kinase 1 / metabolism
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / pathology*
  • DNA Damage / genetics
  • Genomic Instability / genetics
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins / biosynthesis*
  • Intracellular Signaling Peptides and Proteins / genetics
  • MCF-7 Cells
  • Stress, Physiological / genetics
  • Stress, Physiological / physiology*


  • Adaptor Proteins, Signal Transducing
  • CLSPN protein, human
  • Cell Cycle Proteins
  • Intracellular Signaling Peptides and Proteins
  • TIMELESS protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • Checkpoint Kinase 1